Preparation of 6-keto-delta5(10)-19-nor steroids



United States Patent 3,314,943 PREPARATION OF 6-KET0-A -19-N0R STEROIDSAlbert Bowers and Otto Halpern, Mexico City, Mexico,

assignors to Syntex Corporation, Panama, Panama,

a corporation of Panama No Drawing. Filed July 9, 1963, Ser. No. 293,891

8 Claims. (Cl. 260-23955) The present invention relates to a novelprocess for making cyclopentanoperhydrophenanthrene derivatives.

More particularly, the present invention relates to a process for making6-keto-A -19-nor steroids of the androstane, pregnane and sapogeninseries from the corresponding 3-acyloxy-19-hydroxy-A -compounds.

The compounds obtained by the process of the present invention have goodpharmacological properties, besides, they are valuable intermediates inthe synthesis of numerous valuable ring A aromatic steroids or 19-norcompounds, which are well known therapeutic agents.

As set forth in copending application Ser. No. 236,724 filed on Nov. 9,1962 now United States Patent 3,206,460, 6-keto-A -l9-nor androstanesare anabolic-androgenic compounds with a favorable anabolic-androgenicratio in addition to having anti-gonadotrophic, anti-estrogenic,anti-fibrillatory and appetite stimulating properties. The 6-keto-A-19-nor21-desoxy pregnanes are progestational agents which also haveanti-androgenoic, antiestrogenic and anti-gonadotrophic properties. The6-keto- A -19nor-2l-hydroxy pregnanes are cortical hormones withanti-inflammatory activity. The 6-keto-A -19- nor sapogenins produced bythe novel method object of the invention are useful intermediates forthe preparation of the 6-keto-A -19-nor pregnanes by the conventionalsapogenin side chain degradation. Thus, for example, the 3-acylate of A-19-nor-22-isospirosten-3,B-ol-6-one 'isreduced with lithium aluminumhydride, the sapogenin side chain is degraded by the usual procedure toproduce 19-nor-A -pregnadien-3fl,6-diol-20-one, the l7oc-hydroxy groupis introduced by the method of Julian, that is, epoxidation withalkaline hydrogen peroxide, the epoxide ring is opened with hydrogenbromide followed by debromination with Raney nickel to produce M -19-nor-pregnene-3fi,6;9,17a-triol-20-one. Upon selective oxidation of thehydroxyl group at C-6 with manganese dioxide or2,3-dichloro-5,6-dicyano-l,4-benzoquinone, there is formed A-19-nor-pregnene-3;3,17a-dio1-6,20-dione. There can also be introduced a21-acetoxy function in the latter compound by the method of Ringold etal. described in J. Amer. Chem. Soc. 80, 250 (1958). There can furtherbe introduced an llfi-hydroxyl group via conventional microbiologicalhydroxylation.

In copending patent application Serial No. 236,724, filed on November 9,1962, there was described a method for making A -19-nor-6-keto steroidsfrom Son-bromo- 6,8,19-oxido-3-acyloxy compounds, which involvesoxidation With chromium trioxide in aqueous acetic acid to produce the16,19-lactone of the corresponding 5a-bromo- 6fi-hydroxy-l9-oic acid,treatment of these acids with a strong base, preferably with aconcentrated solution of potassium hydroxide in methanol to give rise tothe corresponding 19-nor-A -6a-hydroxy compounds, which upon oxidationwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are converted into therespective A -19-nor- 6-keto-3-hydroxy derivatives.

In accordance with the present invention, the surprising discovery hasbeen made that when a 3-acyloxy-l9-hydroxy-A -compound of theandrostane, pregnane or sapogenin series is treated with an oxidationagent, preferably with a chromic acid derivative, for a prolonged periodof time, there are produced, in one single step, the desired 3,314,943Patented Apr. 18, 1967 A -19-nor-6-keto-3-acyloxy compounds in very goodyields.

The novel method is illustrated by the following equation, wherein onlyrings A and B of the steroid molecule are represented:

In the above formulas R represents an acyl radical of less than 12carbon atoms; preferably the acetyl radical.

In practicing the process hereinbefore illustrated, a 19-hydroxy-3-acyloxy-A -steroid compound of the androstane, pregnane orsapogenin series (I) is treated with an oxidation agent, preferably withchromium trioxide in a suitable organic solvent, at room temperature andfor a prolonged period of time, in the order of 24 hours to seven days,thus affording the corresponding M -19- nor-6-keto-3-acyloxy compounds(II).

As it is well known in the art, oxidations with chromic acid areeffected generally using as solvents aqueous acetic acid, pyridine (thechromium trioxide pyridine complex is formed) or acetone in the presenceof sulfuric acid (Jones oxidation). The best results are obtained byusing the chromium trioxide pyridinecomplex, at room temperature and fora period of time of between 24 hous to seven days, preferably for 5days. However, this reaction may be carried out for a shorter period oftime, in the order of 3 to 6 hours, at higher temperatures, i.e.,between 50 and 70 C. The process may also be accelerated by bubbling airor oxygen through the reaction mixture, for a period of time of 16 to 24hours, at room temperature.

The reaction solution is filtered through celite to separate theinorganic material, and the filtrate is diluted with an organic solventnon-miscible with water, such as for example with ether, ethyl acetate,methylene dichloride, and the like. The organic solution is: then washedwith Water to neutrality, and the product is isolated by the usualmethods, preferably by direct crystallization or chromatography.

When the oxidation is carried out using Jones reagent (8 N chromic acidsolution in acetone and in the presence of sulfuric acid), the reactionmixture is kept at rooom temperature for 5 to 24 hours.

The conversion of 19-hydroxy-3-acyloxy-A -steroids into thecorresponding A -19-nor-6-keto-compounds may also be effected withsodium or potassium dichromate in mixture of benzene-acetic acid or inthe presence of dilute sulfuric acid; however, lower yields areobtained.

Essentially, any 19-hydroxy-3-acyloxy-A -steroid containing from 19 to27 carbon atoms in. the molecule may be used as starting materials inthe operation of the present invention. Thus, for example, at C-17 theremay be present a keto group; a 17fl-acyloxy group; a 17/3-hydroxy groupwith or without an alkyl, alkenyl or alkinyl substituent at C-17a; a17B-acetyl group with or without a hydroxy or acyloxy radical at C-17a;a dihydroxy acetone side chain preferably protected by a17,20;20,21-bismethylenedioxy group, or a sapogenin side chain. At C11there may be present a keto group, at 0-16 a keto group, a hydroxyl(acyloxy) group, an a or 5 methyl radical, a 16a,17a-acetonide group,etc.

The starting materials for the process of the present nvention areobtained in accordance with US. Patent No. 3,065,228, by reaction of the5o -bromo-6,B,19-oxido :ompounds with zinc in ethanol or any otheraliphatic lower alcohol solution.

Examples of suitable starting materials are: the 3,17- diacetate of A-androstene-3B,17B,19-triol, the 3-acetate of 17a-methyl-A -androstene-36,17[i,l9-triol, the 3-acetate of l7a-vinyl-A-androstene-3B,17B,19-triol, the 3-acetate of17a-ethinyl-M-androstene-3/3,175,19-triol, the 3-acetate of A-pregnene-3fi,19-diol-20-one, the 3-acetate of 16amethyl-A-pregnene-3fi,19-diol-20-one, the 3,17-diacetate of 16B-methyl-A-pregnene-3,6,l9-diol-2O-one, the 3-acetate of 16a,17uisopropylidenedioxy A pregnene 3d, l9-diol-20-one, the 3,17-diacetate ofA -pregnene-3fi,17tx, 19-triol-20-one, the 3-acetate of17,20;20,2l-bismethylenedioxy-A pregnene-3fi,19-diol, the 3-acetate of17,20;20, 2l-bismethylenedioxy-A -pregnene-3,8,19-diol-1l-one, and the3-acetate of 19-hydroxy diosgenin.

In the compounds possessing the dihydroxy acetone side chain protectedby the bismethylenedioxy group, the protecting group may be eliminatedby known methods, preferably by reaction with 60% formic acid.

The 3-acyloxy-A -6-keto-19-nor steroids obtained by the novel method maybe saponified, and the free compounds thus obtained oxidized with 8. Nchromic acid in acetone solution to the corresponding 3-ketone.

The follwoing specific examples serve to illustrate, but are notintended to limit the scope of the present invention:

PREPARATION 1 A solution of 5 g. of A -androstene-3fi,19-diol-17-one(described in US. Patent 3,065,228), in 250 cc. of benzenethiophene-free, was treated with 27.5 cc. of a 4 N solution of methylmagnesium bromide in ether and the mixture was refluxed for 3 hours inthe absence of moisture. The cooled mixture was treated carefully withan excess of an aqueous solution of ammonium chloride and the productisolated by ethyl acetate extraction.

The extract was washed with water, died over anhydrous sodium sulfateand evaporated to dryness. Recrystallization of the residue frommethylene chloride-hexane gave 17ot-methyl-A-androstene-3B,17B,19-triol.

In accordance with the foregoing procedure, but substituting methylmagnesium bromide by ethinyl magnesium bromide and vinyl magnesiumbromide, A -andro stone-3,8,19-diol-l7-one gave respectively17a-ethinyl-A androstene-3/3,17fi,19-triol and 17a-vinyl-A -androstene-313,175,19-triol.

PREPARATION 2 A mixture of 3 g. of 17Ot-mIhyl-A -andIOSt6n63B,17B,19-triol, 12 cc. of pyridine and 6 cc. of acetic anhydride was allowedto stand at room temperature overnight, poured into water and the formedprecipitate collected by filtration, thus affording the 3,19-diacetateof 17zx-methyl- A -androstene-3/3,175,19-triol.

The foregoing crude diacetate was dissolved in 100 cc. of methanol,cooled to C. and 500 mg. of potassium carbonate dissolved in cc. ofwater were added. The reaction mixture was kept at 0 C. for 1 hour,neutralized with acetic acid and concentrated to a small volume, dilutedwith water and the formed precipitate filtered olf. Recrystallizationfrom acetone-hexane gave the 3-monoacetate of 17tx-methyl-A-androsteneB,176,19-triol.

In the same manner starting from 17a-vinyl-A -androstene-3B,17B,19-trioland 17wethinyl-M-androstene-35- 17{3,19-triol there were obtained thecorresponding 3- monoacetates.

PREPARATION 3 In accordance with the method described in the precedingpreparation, 2 g. of 19-hydroxy diosgenin were converted into its3-monoacetate, i.e., the 3-acetate of A 22-isospirosten-3B,l9-diol.

I 4 Example I A solution of 2 g. of the 3,17-diacetate of A-androstene-3fi,17/3,19-triol in 20 cc. of pyridine was added to amixture of 2 g. of chromium trioxide in 20 cc. of pyridine. The reactionmixture was kept at room temperature for 7 days; at the end of this timeit was diluted with ethyl acetate, filtered through celite and thefiltrate washed well with water, dried and evaporated to dryness. Theresidue was crystallized from acetone-hexane to give the diacetate of A-l9-nor-androstene-3fi,17fi-diol-6-one.

Example 11 The preceding example was repeated, but the reaction mixturewas allowed to stand for 5 days, to produce also the diacetate of M-19-nor-androstene-3B,l7fi-diol-6- one in similar yield.

Example III A solution of 500 mg. of the 3,17-diacetate of A-androstenc-3B,17;3,l9-triol in 5 cc. of pyridine was added to a mixtureof 500 mg. of chromium trioxide in 5 cc. of pyridine, and the reactionmixture heated on a water bath at 60 C. for 4 hours, under nitrogenatmosphere; it was then diluted with ethyl acetate, filtered throughcelite and the filtrate was washed well with water, dried, evaporated todryness and crystallized from acetone-hexane, to produce also thediacetate of A -19-nor-androstene-35, 17 8-diol-6-one.

Example IV Example I was repeated but the reaction mixture was kept for24 hours only, to produce also the diacetate of A-19-nor-androstene-3B,17,8-diol-6-one.

Example V In accordance with the method described in Example I, thecompounds below mentioned (I) were treated with chromic acid inpyridine, thus producing the compounds under II.

I II

3-m0noacetate of 17,20;20,21-

bismethylenedioxy-A -pregnene- 35,19-di0l-11-0ne.

3-mon0acetate of 17,20;20,21-

bismethylenedioxy-A -pregnenc- 36,19-di01.

3-monoacetate of A -androstene- 35,19-di0l-17-one.

3-monoacetate 0i 17a-n1ethyl-A androstene'3B,17fl,19-triol.

3-monoacetate of 17x-vinyl-A androstene-3fi,175,19-tri01.

3-monoacetate 0i lg-liydroxydiosgenin.

Example VI A solution of 1 g. of chromium trioxide in 5 cc. of aceticacid was added dropwise to a stirred solution of 1 g. of the3,17-diacetate of A -androstene-3fi,l7fl, 19-triol in 10 cc. of glacialacetic acid while maintaining the temperature around 20 C. After 12hours at room temperature the mixture was poured into ice water and theformed precipitate filtered off, washed with water and recrystallizedfrom methanol, thus giving the diacetate of A-l'9-nor-androstene-3fi,17fi-diol-6-one.

Example VII A solution of 1 g. of the 3-monoacetate of A -pregnene-3,8,19-diol-20-one in 20 cc. of acetone was cooled to C., and thentreated under nitrogen atmosphere and with stirring with an 8 N solutionof chromic acid (prepared by mixing 26 g. of chromium trioxide with 23cc. of con centrated sulfuric acid and dilution with water to 100 cc.)until the color of the reagent persisted in the mixture. It was stirredfor hours further at room temperture and diluted with water, extractedwith methylene chloride and washed with water to neutrality, dried withanhydrous sodium sulfate and evaporated to dryness. The residue waschromatographed on 30 g. of washed alumina to produce the acetate of A-19-nor-pregnen- 3fl-ol-6,20-dione identical to that obtained by themethod of Example V.

Example VIII To a solution of 1.5 g. of the 3,17-diacetate of A-androstene-3,8,l7fl,19-triol in 50 cc. of benzene there was addeddropwise 2 g. of sodium dichromate bihydrate dis1 solved in 50 cc. ofacetic acid, while maintaining the temperature between 18 C., and thereaction mixture was allowed to stand at room temperature for 24 hours.It was then diluted with ether and washed with water to neutral, driedover anhydrous sodium sulfate and evaporated to dryness under reducedpressure. The residue was chromatographed on 50 g. of washed alumina toproduce the diacetate of A -l9-nor-androstene-3B,17fldiol-6-one,identical to that obtained in Example I.

Example IX The preceding example was repeated but the reaction mixturewas kept for 3 days at room temperature, to afford the same product.

Example X Example VII was repeated but the reaction time was extended to18 hours, to give the same product in similar yield.

Example XI Example XII Example IV was repeated but bubbling constantly astream of oxygen through the reaction mixture, to produce also thediacetate of A -19-nor-androstene-3B, 17B-diol-6-one in similar yields.

In another experiment oxygen was substituted by a stream of air, withthe same results.

Example XIII One g. of the acetate of 17,20;20',2l-bismethylenedioxy-A-19-11orpregnen-3fi-ol- 6-one with 20 cc of formic acid was heated onthe steam bath for 1 hour, cooled, diluted with water and the formedprecipitate collected by filtration, washed with water, dried andrecrystallized from acetone-hexane thus yielding the 3- acetate of A 19nor pregnene 3fi,17a,21 triol- 6,20-di0ne.

In the same manner, the acetate of l7,20;20,2l-.bismethylenedioxy A 19nor pregnen 3B ol- 6,l1-dione was converted into the 3-acetate of A -19-nor-pregnene-3fi,l7a,21-triol-6,l1,20-trione.

We claim:

1. A process for the production of 3-acyloxy 6-keto- A -19-norsteriodsselected from the group consisting of the androstane, pregnane andsapogenin series which comprises reacting a 3-acyloxy-A -l9-hydroxysteroid selected from the group consisting of the androstane, pregnaneand sapogenin series with an excess of an oxidation agent derived fromchromic acid for at least 3 hours.

2. The process of claim 1 wherein the 'chromic acid derivative is thechromium trioxide pyridine complex.

3. The process of claim 11 wherein the oxidation agent is chromiumtrioxide in aqueous acetic acid.

4. The process of claim 1 wherein the oxidation agent is chromiumtrioxide in acetone-sulfuric acid solution.

5. The process of claim 1 wherein the oxidation agent is sodiumdichromate.

6. The process of claim 2. wherein the reaction is effected at roomtemperature for a period of time in the order of 24 hours to 7 days.

7. The process of claim 2 wherein the reaction is conducted at atemperature higher than room temperature, for a period of time ofbetween 4 and 24 hours.

8. The process of claim 2 wherein the reaction is accelerated bybubbling oxygen through the reaction mixture.

References Cited by the Examiner UNITED STATES PATENTS 3,178,419 4/1965Jeger et al. 260239.55 3,212,969 10/1965 Bowers 167--58 OTHER REFERENCESFieser and Fieser: Steroids, N.Y., Reinhold, 1959, pages 202, 203, and472.

Hagiwara et al: Chem. Pharm. Bull. (Tokyo), 8, pp. 84 and 85 (1960).

ELBERT L. ROBERTS, Primary Examiner. T. M. MESHBESHER, AssistantExaminer.

1. A PROCESS FOR THE PRODUCTION OF 3-ACYLOXY6-KETO$5(10)-19-NOR-STERIODS SELECTED FROM THE GROUP CONSISTING OF THEANDROSTANE, PREGANE AND SAPOGENIN SERIES WHICH COMPRISES REACTING A3-ACYLOXY-$5-1.-HYDROXY STEROID SELECTED FROM THE GROUP CONSISTING OFTHE ANDROSTANE, PREGANE AND SAPOGENIN SERIES WITH AN EXCESS OF ANOXIDATION AGENT DERIVED FROM CHROMIC ACID FOR AT LEAST 3 HOURS.